Songbirds have been a rich experimental system for studying neurobiological questions of relevance to human health for decades. In particular, songbirds are the leading non-human model for the investigation of the biological basis of vocal learning, a critical behavioral substrate for speech acquisition. In addition, songbirds are an ideal system for the study of brain asymmetry, hormonal control of brain development, physiological function of sleep, and sex-specific differences in the brain, behavioral-induced gene expression and adult neurogenesis, among other questions. Nonetheless despite their importance for neurobiology, the usefulness of songbirds as an experimental system has been restricted by a lack of genetic manipulation methods. Recently we have succeeded in applying lentiviral-mediated transgenesis to zebra finches (Agate et al., 2009). While this achievement proves the feasibility of lentiviral-mediated transgenesis in songbirds, the current method is inefficient, labor-intensive and costly. In this proposal we plan to optimize the existing strategy and to generate novel tools to develop a practical avian transgenic technique that could be used by other songbird neurobiology laboratories. The ability to perform genetic manipulations in songbirds will open unparalleled opportunities for the study of the relationship between genes and brain function in an animal species with a robust behavioral repertoire. Transgenic songbirds will allow us to generate animal models of human diseases affecting complex cognitive functions and communication disorders, which can only be incompletely modeled in other animal species. PUBLIC HEALTH RELEVANCE: The main manifestation of many neurological and psychiatric disorders in humans is altered behavior. The rich behavioral repertoires exhibited by songbirds make them ideal animal's nriodels in which to mimic human diseases that affect behavior. We propose to develop new molecular tools that will allow for genetic manipulation of songbirds to generate animal models of human diseases that affect complex cognitive functions and communication disorders.